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P450: Regulation and Polymorphisms

Research Summary

Joyce A. Goldstein, Ph.D., heads the Human Metabolism Group and holds a secondary appointment in the NIEHS Epigenetics and Stem Cell Biology Laboratory. The Human Metabolism Group studies function, transcriptional regulation and genetic polymorphisms of the human cytochrome P450 enzymes (CYPs) which metabolize foreign compounds such as clinically-used drugs, herbal medicines, and environmental chemicals such as pesticides and herbicides. Our group has pioneered studies of the human CYP2C subfamily which includes four members: CYP2C8, CYP2C9, CYP2C18 and CYP2C19. These enzymes metabolize approximately 20% of clinically known drugs as well as over-the-counter remedies such as ibuprofen and the antiulcer drug omeprazole. The CYP2C enzymes also metabolize endogenous compounds such as and retinoic acid and metabolize arachidonic acid to biologically active intermediates.

Polymorphisms in the genes for CYP enzymes lead to inter-individual variability in the ability of humans to metabolize drugs and environmental chemicals. This can lead to adverse drug reactions, one of the major sources of death in humans. Polymorphisms affect the half-life, efficacy and toxicity of clinically-used drugs and can potentially affect susceptibility to environmentally-caused disease states such as cancer. Identification of genetic defects and development of genetic tests which identify polymorphisms are a prerequisite to identifying whether certain individuals are at high risk to adverse effects of clinically used drugs and other xenobiotics. Identifying polymorphisms in CYP enzymes is now used to determine mines risks of new drugs to susceptible individuals in clinical trials, and also holds promise for individualized medicine in the future.

The group currently studies the regulation of the CYP2C genes and proteins both constitutively in hepatic and extrahepatic tissues, and the upregulation by prior exposure to drugs such as rifampicin, phenobarbital, herbal medicines, glucocorticoids as well as environmental compounds. This up regulation is a source of drug-drug interactions, and a second source of variation in CYP metabolism in humans. We examine the molecular mechanism of these changes, analyzing promoter activity by a variety of techniques, and have identified receptors such as the constitutive androstane receptor (CAR), the pregnane X receptor ( PXR), hepatic nuclear factor 4α(HNF4 and co-regulators such as NCOAX6 which modulate interaction of these receptors with DNA, studying both protein-protein and protein-DNA interactions.

The laboratory has identified cross-talk between HNF4alpha and the xenosensing receptors CAR and PXR. A major effort to identify HNF4 interacting proteins, which influence the synergy between these receptors, identified NCOA6 which is thought to bridge these sites. More recently, the group identified a variable member of the Mediator complex, Med25, as the HNF4alpha-interacting protein which brings the Mediator complex and polymerase II to the proximal HNF4 sites in CYP2C9 and other select genes, which control drug and lipid metabolism and some transporters. Not all genes regulated by HNF4alpha are regulated by Med25. A major effort is underway to understand how Med25 interacts only with select HNF4 sites on the promoters of various genes to initiate transcription.

Major area of research:

The function, transcriptional regulation and genetic polymorphisms of CYP2C enzymes

Current projects:

Assessment of the ability of the human and murine CYP2Cs to metabolize clinical drugs, environmental compounds and endogenous compounds

Discovery and functional assessment of polymorphisms in the human CYPs in recombinant studies in vitro and in clinical studies in humans.

Prospective studies of influence of CYPC polymorphisms: e.g., the risk of adverse drug reactions to warfarin and other drugs

The transcriptional up-regulation of the CYP2C subfamily by nuclear orphan receptors such as the constitutive androgen receptor (CAR), the pregnane X receptor (PXR), hepatic nuclear factor 4α, and other nuclear receptors which also lead to inter-individual variability and drug-drug interactions

Identifying co-regulators such as NCOA6 and co-repressors which are involved in protein-protein and protein-DNA interactions thus modulating regulation of CYP2C enzymes

Regulation of CYP enzymes constitutively and in response to physiological stress and disease

Goldstein received her Ph.D. in pharmacology from the University of Texas Southwestern Medical School, at Dallas, Texas in 1968. She holds two patents on the discovery of CYP2C19 and the major polymorphism in this enzyme, and has published over 154 peer-reviewed articles in leading biomedical journals, as well as 25 book chapters. She is an ISI Highly Cited Author in Pharmacology (since 2006) a member of the Faculty of 1000, and is Board Certified by the American Board of Toxicology. She was formerly the Acting Chief of the Biochemistry Branch at EPA, Research Triangle Park, North Carolina before joining NIEHS in 1977.